Characterizing the neuroanatomical abnormalities of schizophrenia has played a critical role in forming our current understanding of the pathophysiology of schizophrenia. While there is substantial evidence that these neuroanatomical abnormalities begin with a neurodevelopmental defect, there is also evidence that the magnitude and pattern of such abnormalities progresses over time, presumably because of an ongoing neurodegenerative process. This is an application for renewal of a research project that has been ongoing for 8 years. The initial goal of the project was to more precisely define neuroanatomical abnormalities that occur in schizophrenia by using the tools of computational anatomy. During the initial funding period of this project (8/1/98 to 7/31/01), we demonstrated the feasibility of using high dimensional brain mapping (HDBM) to characterize abnormalities of the volume, shape, and asymmetry of the hippocampus in subjects with schizophrenia. During the second funding period of this project (8/1/01 to present), we extended the use of HDBM to demonstrate abnormalities of the thalamic complex as well, and to link these abnormalities with abnormalities of cognition and brain activation. Also, we developed and implemented a new method for cortical analysis - Labeled Cortical Mantle Depth Mapping (LCMDM) - to characterize structural abnormalities of the cingulate gyrus in schizophrenia subjects. Finally, it was a major goal of our second funding period to collect longitudinal data in our schizophrenia and control subjects, and look for evidence of time-dependent changes in specific neuroanatomical measures. To date, we have found evidence for progressive gray matter volume loss in the cingulate gyrus and progressive shape deformation of the hippocampus and thalamus in schizophrenia subjects as compared to control subjects (see Progress Report). Our aims for the third period of funding are to use HDBM and LCMDM to further define the distribution of static versus progressive neuroanatomical abnormalities in schizophrenia subjects (e.g., to test the hypothesis that progressive gray matter loss is confined to fronto-temporal structures). We also propose preliminary studies to link progressive changes in neuroanatomical measures in schizophrenia subjects with time-dependent changes in psychopathology and cognition, and with genetic polymorphisms that can influence neuronal survival.